The emergent role of mitochondrial <scp>RNA</scp> modifications in metabolic alterations

Boughanem, Hatim; Böttcher, Yvonne; Tomé‐Carneiro, João; Hazas, María-Carmen López de Las; Dávalos, Alberto; Çayır, Akın; Macías-González, Manuel

doi:10.1002/wrna.1753

Cited by 13 publications

(16 citation statements)

References 142 publications

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“…Interestingly, in line with Van Der Wijst et al, we found that essentially only mitochondrial GpC methylation induces a minor downregulation of selective mitochondrial genes (Supplementary Figure S2) [27]. In addition, recent papers show that, besides correct transcription, mitochondrial protein translation and therefore mitochondrial function are also dependent on correct post-transcriptional RNA modifications [41,42]. Furthermore, we found that mitochondrial GpC and, to a lesser extent, CpG methylation specifically increase nuclear bile acid metabolic gene expression.…”

Section: Discussionsupporting

confidence: 89%

Mitochondrial GpC and CpG DNA Hypermethylation Cause Metabolic Stress-Induced Mitophagy and Cholestophagy

Theys,

Ibrahim,

Mateiu

et al. 2023

IJMS

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Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by a constant accumulation of lipids in the liver. This hepatic lipotoxicity is associated with a dysregulation of the first step in lipid catabolism, known as beta oxidation, which occurs in the mitochondrial matrix. Eventually, this dysregulation will lead to mitochondrial dysfunction. To evaluate the possible involvement of mitochondrial DNA methylation in this lipid metabolic dysfunction, we investigated the functional metabolic effects of mitochondrial overexpression of CpG (MSssI) and GpC (MCviPI) DNA methyltransferases in relation to gene expression and (mito)epigenetic signatures. Overall, the results show that mitochondrial GpC and, to a lesser extent, CpG methylation increase bile acid metabolic gene expression, inducing the onset of cholestasis through mito-nuclear epigenetic reprogramming. Moreover, both increase the expression of metabolic nuclear receptors and thereby induce basal overactivation of mitochondrial respiration. The latter promotes mitochondrial swelling, favoring lipid accumulation and metabolic-stress-induced mitophagy and autophagy stress responses. In conclusion, both mitochondrial GpC and CpG methylation create a metabolically challenging environment that induces mitochondrial dysfunction, which may contribute to the progression of MASLD.

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Section: Discussionsupporting

confidence: 89%

Mitochondrial GpC and CpG DNA Hypermethylation Cause Metabolic Stress-Induced Mitophagy and Cholestophagy

Theys,

Ibrahim,

Mateiu

et al. 2023

IJMS

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“…It is only a small step to suggest that is also the case for arginine glycosylation reactions that are well-established in many pathogenic bacteria . Last, but by no means least, methylation of trigonal, planar nitrogens to give N -6 adenosine and N -4 cytidine nucleobases in DNA and RNA, respectively, is a feature of epigenetic activation. − …”

Section: Discussionmentioning

confidence: 97%

Arginine Kinase Activates Arginine for Phosphorylation by Pyramidalization and Polarization

Falcioni,

Molt,

Jin

et al. 2024

ACS Catal.

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Arginine phosphorylation plays numerous roles throughout biology. Arginine kinase (AK) catalyzes the delivery of an anionic phosphoryl group (PO3 –) from ATP to a planar, trigonal nitrogen in a guanidinium cation. Density functional theory (DFT) calculations have yielded a model of the transition state (TS) for the AK-catalyzed reaction. They reveal a network of over 50 hydrogen bonds that delivers unprecedented pyramidalization and out-of-plane polarization of the arginine guanidinium nitrogen (Nη2) and aligns the electron density on Nη2 with the scissile P–O bond, leading to in-line phosphoryl transfer via an associative mechanism. In the reverse reaction, the hydrogen-bonding network enforces the conformational distortion of a bound phosphoarginine substrate to increase the basicity of Nη2. This enables Nη2 protonation, which triggers PO3 – migration to generate ATP. This polarization–pyramidalization of nitrogen in the arginine side chain is likely a general phenomenon that is exploited by many classes of enzymes mediating the post-translational modification of arginine.

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“…To identify both the MRM-related signature and the 16 gene signatures mentioned above, the “GSVA” R package was utilized to carry out single-sample gene set enrichment analysis (ssGSEA) 18 . The MRM-related genes were obtained from previous research 8 . The ssGSEA was used to quantify immune cell infiltration based on bulk RNA-seq data.…”

Section: Methodsmentioning

confidence: 99%

“…Accumulated evidence shows that different mitochondrial RNAs (e.g., rRNA, tRNA, or mRNA) can be extensively modified. Each modification is highly regulated and involves various regulatory proteins 8 – 11 . MRM is essential for maintaining cellular metabolic pathways and overall cell homeostasis, which, if disrupted, can lead to disease 12 .…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial RNA modification-based signature to predict prognosis of lower grade glioma: a multi-omics exploration and verification study

Zhou,

Ling,

Cui

et al. 2024

Sci Rep

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Mitochondrial RNA modification (MRM) plays a crucial role in regulating the expression of key mitochondrial genes and promoting tumor metastasis. Despite its significance, comprehensive studies on MRM in lower grade gliomas (LGGs) remain unknown. Single-cell RNA-seq data (GSE89567) was used to evaluate the distribution functional status, and correlation of MRM-related genes in different cell types of LGG microenvironment. We developed an MRM scoring system by selecting potential MRM-related genes using LASSO regression analysis and the Random Survival Forest algorithm, based on multiple bulk RNA-seq datasets from TCGA, CGGA, GSE16011, and E-MTAB-3892. Analysis was performed on prognostic and immunological features, signaling pathways, metabolism, somatic mutations and copy number variations (CNVs), treatment responses, and forecasting of potential small-molecule agents. A total of 35 MRM-related genes were selected from the literature. Differential expression analysis of 1120 normal brain tissues and 529 LGGs revealed that 22 and 10 genes were upregulated and downregulated, respectively. Most genes were associated with prognosis of LGG. METLL8, METLL2A, TRMT112, and METTL2B were extensively expressed in all cell types and different cell cycle of each cell type. Almost all cell types had clusters related to mitochondrial RNA processing, ribosome biogenesis, or oxidative phosphorylation. Cell–cell communication and Pearson correlation analyses indicated that MRM may promoting the development of microenvironment beneficial to malignant progression via modulating NCMA signaling pathway and ICP expression. A total of 11 and 9 MRM-related genes were observed by LASSO and the RSF algorithm, respectively, and finally 6 MRM-related genes were used to establish MRM scoring system (TRMT2B, TRMT11, METTL6, METTL8, TRMT6, and TRUB2). The six MRM-related genes were then validated by qPCR in glioma and normal tissues. MRM score can predict the malignant clinical characteristics, abundance of immune infiltration, gene variation, clinical outcome, the enrichment of signaling pathways and metabolism. In vitro experiments demonstrated that silencing METTL8 significantly curbs glioma cell proliferation and enhances apoptosis. Patients with a high MRM score showed a better response to immunotherapies and small-molecule agents such as arachidonyl trifluoromethyl ketone, MS.275, AH.6809, tacrolimus, and TTNPB. These novel insights into the biological impacts of MRM within the glioma microenvironment underscore its potential as a target for developing precise therapies, including immunotherapeutic approaches.

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The emergent role of mitochondrial RNA modifications in metabolic alterations

Cited by 13 publications

References 142 publications

Mitochondrial GpC and CpG DNA Hypermethylation Cause Metabolic Stress-Induced Mitophagy and Cholestophagy

Mitochondrial GpC and CpG DNA Hypermethylation Cause Metabolic Stress-Induced Mitophagy and Cholestophagy

Arginine Kinase Activates Arginine for Phosphorylation by Pyramidalization and Polarization

Mitochondrial RNA modification-based signature to predict prognosis of lower grade glioma: a multi-omics exploration and verification study

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